Department of Hematology and Medical Oncology, University Medical Center Goettingen, Goettingen, Germany.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
Blood. 2019 Feb 7;133(6):566-575. doi: 10.1182/blood-2018-07-865527. Epub 2018 Nov 29.
There is a pressing need for more effective therapies to treat patients with T-cell lymphomas (TCLs), including first-line approaches that increase the response rate to cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) chemotherapy. We characterized the mitochondrial apoptosis pathway in cell lines and patient-derived xenograft (PDX) models of TCL and assessed the in vitro efficacy of BH3 mimetics, including the BCL2 inhibitor venetoclax, the BCL2/BCL-xL inhibitor navitoclax, and the novel MCL1 inhibitor AZD5991. The abundance of antiapoptotic BCL2 family members based on immunoblotting or RNA transcript levels correlated poorly with the activity of BH3 mimetics. In contrast, the functional approach BH3 profiling reliably predicted sensitivity to BH3 mimetics in vitro and in vivo. We used BH3 profiling to select TCL PDX that were dependent on MCL1. Mice xenografted with these PDX and treated with AZD5991 had markedly improved survival. The combination of AZD5991 and CHOP achieved synergy based on survival improvement beyond a mathematical "sum of benefits" model. Thus, MCL1 inhibition is a promising strategy as both a single agent and in combination with chemotherapy for patients with TCL and functional dependence on MCL1.
迫切需要更有效的疗法来治疗 T 细胞淋巴瘤（TCL）患者，包括增加环磷酰胺、阿霉素、长春新碱和泼尼松（CHOP）化疗反应率的一线方法。我们对 TCL 的细胞系和患者来源的异种移植（PDX）模型中的线粒体凋亡途径进行了表征，并评估了 BH3 模拟物的体外疗效，包括 BCL2 抑制剂 venetoclax、BCL2/BCL-xL 抑制剂 navitoclax 和新型 MCL1 抑制剂 AZD5991。基于免疫印迹或 RNA 转录水平的抗凋亡 BCL2 家族成员的丰度与 BH3 模拟物的活性相关性较差。相比之下，功能方法 BH3 谱分析可靠地预测了 BH3 模拟物在体外和体内的敏感性。我们使用 BH3 谱分析来选择依赖 MCL1 的 TCL PDX。用这些 PDX 异种移植的小鼠并用 AZD5991 治疗，其存活期明显延长。AZD5991 与 CHOP 的联合应用基于存活期的改善，超过了数学“效益总和”模型，实现了协同作用。因此，MCL1 抑制作为单一药物以及与化疗联合治疗 TCL 患者和对 MCL1 功能依赖的患者具有广阔的前景。
